Anti-inflammatory and antinociceptive activities of an acid fraction of the seeds of Carpotroche brasiliensis (Raddi) (Flacourtiaceae).

Carpotroche brasiliensis is a native Brazilian tree belonging to the Oncobeae tribe of Flacourtiaceae. The oil extracted from its seeds contains as major constituents the same cyclopentenyl fatty acids hydnocarpic (40.5%), chaulmoogric (14.0%) and gorlic (16.1%) acids found in the better known chaulmoogra oil prepared from the seeds of various species of Hydnocarpus (Flacourtiaceae). These acids are known to be related to the pharmacological activities of these plants and to their use as anti-leprotic agents. Although C. brasiliensis oil has been used in the treatment of leprosy, a disease that elicits inflammatory responses, the anti-inflammatory and analgesic activities of the oil and its constituents have never been characterized. We describe the anti-inflammatory and antinociceptive activities of C. brasiliensis seed oil in acute and chronic models of inflammation and in peripheral and central nociception. The mixture of acids from C. brasiliensis administered orally by gavage showed dose-dependent (10-500 mg/kg) anti-inflammatory activity in carrageenan-induced rat paw edema, inhibiting both the edema by 30-40% and the associated hyperalgesia. The acid fraction (200 mg/kg) also showed significant antinociceptive activity in acetic acid-induced constrictions (57% inhibition) and formalin-induced pain (55% inhibition of the second phase) in Swiss mice. No effects were observed in the hot-plate (100 mg/kg; N = 10), rota-road (200 mg/kg; N = 9) or adjuvant-induced arthritis (50 mg/kg daily for 7 days; N = 5) tests, the latter a chronic model of inflammation. The acid fraction of the seeds of C. brasiliensis which contains cyclopentenyl fatty acids is now shown to have significant oral anti-inflammatory and peripheral antinociceptive effects.

Synthesis and pharmacological evaluation of novel heterotricyclic acylhydrazone derivatives, designed as PAF antagonists.

This paper describes the synthesis and the antiplatelet properties of new heterotricyclic N-acylhydrazone derivatives (7a-e), structurally analogous to known hetrazepinic PAF antagonists, exploring molecular hybridization as a tool for molecular designing. The synthetic route employed to access compounds (7a-e) used, as starting material, the previously described methyl 3-hydroxy-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno[2, 3-d]pyridine-2-carboxylate derivative. The results from inhibitory effects of these novel acylhydrazone derivatives (7a-e) upon PAF-induced platelet aggregation, indicated that all compounds present a significant antithrombotic profile.

Anti-inflammatory and analgesic activities of the latex containing triterpenes from Himatanthus sucuuba.

Some triterpenes and iridoids were previously isolated from the stem bark of Himatanthus sucuuba. The latex from Himatanthus sucuuba is used in popular amazonian medicine as an anti-inflammatory remedy. Fractions of the latex were pharmacologically evaluated with a view to verify this popular use in the carrageenan-induced rat paw edema and in the acetic acid-induced mouse constriction tests. The hexane fraction inhibited the edema formation by 35.9% at a dose of 200 mg/kg (p.o.) but no activity was observed at 100 mg/kg (p.o.). The triterpenes present in the hexane fraction were identified as lupeol acetate, alpha-amyrin and lupeol cinnamates. The fraction containing only cinnamates inhibited the edema and the abdominal constrictions by 50-40% and 57.9%, respectively, at 100 mg/kg (p.o.). Among all the fractions studied, the fraction containing only cinnamates showed the greatest anti-inflammatory activity which suggests that these compounds were responsible for the previously described activity of the crude extract.

Synthesis and analgesic activity of novel N-acylarylhydrazones and isosters, derived from natural safrole.

Anew series of antinociceptive compounds belonging to the N-acylarylhydrazone (NAH) class were synthesized from natural safrole (7). The most analgesic derivative represented by 10f, [(4'-N,N-dimethylaminobenzylidene-3-(3', 4'-methylenedioxyphenyl)propionylhydrazine], was more potent than dipyrone and indomethacin, used as standards. The NAH compounds described herein were structurally planned by molecular hybridization and classical bioisosterism strategies on previously reported analgesic NAH in order to identify the pharmacophoric contribution of the N-acylarylhydrazone moiety and investigate the structure-activity relationship (SAR) in these series.

Synthesis and pharmacological evaluation of a new class of bicyclic phospholipids, designed as platelet activating factor antagonists.

(+/-)-3-Alkoxymethyl-(2-oxabicyclo[3.3.0]octane)-5-yl-methyl-phosp horyl- ethyl-pyridinium [alkyl chain = methyl (5a) and (5b), allyl (6a) and (6b), n-propyl (7a) and (7b) and n-hexyl (8a) and (8b)] derivatives, structurally designed as conformationally restricted platelet activating factor (PAF) antagonists were synthesized in 12-26% overall yield, using ethyl (+/-)-3-hydroxymethyl-5-(2-oxabicyclo [3.3.0] octane) carboxylate (13a,b) as key intermediate. The anti-platelet profile of the new derivatives was evaluated in a PAF-induced aggregation model in rabbit platelet-rich plasma; only compound 8a exhibited a modest activity.

New pyrazolylhydrazone derivatives as inhibitors of platelet aggregation.

A series of 5-pyrazolylhydrazone derivatives was designed to be mixed hybrid isosteres of both BW755C and CBS-1108, which belong to the class of dual cyclo-oxygenase and 5-lipoxygenase inhibitors. Some derivatives of this series inhibit the in-vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5 microM), collagen (5 micrograms mL-1) and arachidonic acid (100 microM). The structure-activity relationships of this class of compounds were determined from these results. When ADP is used as the aggregation inducer, the presence of free oxygenated substituents at the p-position in the phenyl subunit of the hydrazone moiety favours inhibitory activity; p-methoxyformylbenzene-5-(1-phenyl-3-methyl-4-nitropyrazolyl )hydrazone (100 microM), which has a methoxy group at this position was the most active with 62.8% inhibition of aggregation. In contrast, substitution in the aryl ring does not affect the aggregation induced by collagen, whereas the non-substituted compound, formylbenzene-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydra zon e, showed similar activity to those of substituted derivatives. In the arachidonic acid assays, the presence of an aryl ring linked to the hydrazone moiety, with an adequate electronic density at the ring due to the nature of its substituents, is an important structural requirement for inhibitory activity.

A selective inhibitor of thromboxane synthetase activity of rabbit heart tissue: a pyridazinic derivative.

The effects of 2-(2 dimethylaminoethyl) 5-benzylidene 6-methyl (2H,4H)-3-pyridazinone (III) were studied on the biosynthesis of TXA2 and PGI2 in vitro the TXA2 and PGI2 synthetase activity of heart tissue. Biosyntheses of TXA2 and PGI2 were carried out using arachidonic acid as a substrate and horse platelet and aorta microsomes as sources of TXA2 and PGI2 synthetases respectively. TXB2 and 6-keto PGF1 alpha were determined by RIA. III--did not significantly modify either the biosynthesis of PGI2 in vitro or the PGI2 synthetase activity of heart tissue. did not significantly inhibit TXA2 biosynthesis in vitro but markedly reduced the TXA2 synthetase activity of heart tissue: for a microsomal fraction concentration of 100 micrograms protein, the ID50 was 6.37 X 10(-5) M +/- 1.29 X 10(-8) M. Thus III behaves as a specific inhibitor of the TXA2 synthetase activity of heart tissue and could have a beneficial use in therapeutics.

Comparative study of the biosynthesis of PGE2, PGF2 alpha and TXA2 by different organs of genetically hypertensive (SHR) and obese-hypertensive (SHR-fa/fa) rats.

As an experimental model, we used 6-week-old genetically obese-hypertensive rats (SHR-fa/fa) which were obtained by transferring the fatty/fa gene of hyperlipaemic obese rats into the genome of the SHR strain: the SHR-fa/fa were bigger and more hypertensive than their SHR littermates. Studying the capacity of the hearts, kidneys, spleens, brains and lungs to synthesize PGE2, PGF2 alpha and TXA2, enabled us to show that the hearts and lungs of SHR-fa/fa synthesized more PG than those of SHR; SHR-fa/fa brains generated less icosanoids than those of SHR; the amounts of PGE2 and TXA2 produced by the kidneys are similar in SHR and in SHR-fa/fa. From the experimental data we can infer that the introduction of the fatty/fa gene into the genome of SHR does not significantly alter the capacity of the kidneys to synthesize icosanoids; the more severe hypertension in the SHR-fa/fa would result from an increase in TXA2 biosynthesis by cardiac tissue which, at the same time, synthesized more PGE2, which could be a means of defence against hypertension. Moreover this genetical manipulation inhibited the icosanoid-synthesizing capacity of the brain which thus attenuated the central nervous system activity of the animals.

Study of the PG E2 synthetase activity of different regions of dog and rabbit hearts.

Prostaglandin E2 synthetase activity of the microsomal fraction from different parts of dog and rabbit heart was tested with 3H-arachidonic acid as substrate. PG E2 synthesized was separated and purified by TLC and determined by the radiometric method or by bioassay. In the experimental conditions adopted, it was shown that the heart tissue is endowed with an enzyme system capable of synthesizing PG E2 but this PG E2 synthetase activity is not uniformly distributed in the different parts of the heart. It is highest in the right atrium and the activity of the atria is higher than that of the ventricles. It is species-dependent. The closely similar repartition of PG E2 synthetase activity and sympathetic nerve endings strongly suggests that PG E2 modulates adrenergic neurotransmission in the heart.

Enhanced prostacyclin biosynthesis and decreased thromboxane formation by 3-dimethylamino 5-(2',6'-dichlorobenzylidene) 6-methyl (4H)-pyridazine (PC 89).

The effects of 3-dimethylamino 5-(2',6'-dichlorobenzylidene) 6-methyl (4H)-pyridazine (PC 89) on the biosynthesis of PG I2 and TX A2 using horse aorta and horse platelet microsomes as sources of enzymes and arachidonic acid as substrate, were investigated. PC 89 (1.10(-6) M- 1.10(-3) M) dose-dependently - enhanced the biosynthesis of PG I2: the AD50 was 6.8 X 10(-6) M +/- 1.2 X 10(-9) M, the Vmax did not vary significantly with concentrations: PC 89 increased the affinity of enzyme for substrate - but inhibited TX A2 biosynthesis (ID50 = 3.31 X 10(-3) M +/- 4.8 X 10(-7) M): this inhibiting action was not of competitive type. Owing to this dual activity of preventing TX A2 formation and stimulating PG I2 biosynthesis, PC 89 could be a valuable drug for myocardial ischemia and atherosclerosis therapeutics.